Activated Gα13 Impairs Cell Invasiveness through p190RhoGAP-Mediated Inhibition of RhoA Activity

The GTPase RhoA is a downstream target of heterotrimeric G(13) proteins and plays key roles in cell migration and invasion. Here, we show that expression in human melanoma cells of a constitutively active, GTPase-deficient G alpha(13) form (G alpha(13)QL) or lysophosphatidylcholine (LPC)-promoted signaling through G alpha(13)-coupled receptors led to a blockade of chemokine-stimulated RhoA activation and cell invasion that was rescued by active RhoA. Melanoma cells expressing G alpha(13)QL or cells stimulated with LPC displayed an increase in p190RhoGAP activation, and defects in RhoA activation and invasion were recovered by knocking down p190RhoGAP expression, thus identifying this GTPase-activating protein (GAP) protein as a downstream G alpha(13) target that is responsible for these inhibitory responses. In addition, defective stress fiber assembly and reduced migration speed underlay inefficient invasion of G alpha(13)QL melanoma cells. Importantly, G alpha(13)QL expression in melanoma cells led to impairment in lung metastasis associated with prolonged survival in SCID mice. The data indicate that G alpha(13)-dependent downstream effects on RhoA activation and invasion tightly depend on cell type-specific GAP activities and that G alpha(13)-p190RhoGAP signaling might represent a potential target for intervention in melanoma metastasis. [Cancer Res 2008;68(20):8221-30]